Amyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle

TLDR

Amyloid‑β accumulation in the brain is a hallmark of Alzheimer’s disease, yet the factors that regulate its concentration‑dependent aggregation, including changes in interstitial fluid levels, remain only partially understood. In vivo microdialysis in mice showed that interstitial fluid amyloid‑β levels rise with wakefulness, acute sleep deprivation, and orexin infusion, fall with orexin receptor antagonism, and that chronic sleep restriction increases while orexin antagonism decreases amyloid plaque formation, implicating the sleep‑wake cycle and orexin in Alzheimer’s disease pathogenesis.

Abstract

Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease.